The progression of many life-threatening diseases such as cancer, AIDS, infectious diseases, immune disorders and cardiovascular disorders are influenced by multiple molecular mechanisms. Due to this complexity, achieving cures with a single agent has been met with limited success. Thus, combinations of agents have often been used to combat disease, particularly in the treatment of cancers. It appears that there is a strong correlation between the number of agents administered and cure rates for cancers such as acute lymphocytic leukemia and metastatic colorectal cancer (Frei, et al., Clin. Cancer Res. (1998) 4:2027-2037; Fisher, M. D., Clin. Colorectal Cancer (2001) 1:85-86). In particular, chemotherapeutic agents in combination with potentiating agents, such as heat shock protein inhibitors have been used to successfully treat a number of cancers in the clinic.
Taxanes are a class of widely used anticancer drugs. They are naturally produced by plants belonging to the Taxus genus (e.g., Yews). “Taxanes” include paclitaxel, docetaxel, cabazitaxel and other taxane analogs or derivatives thereof.
Potentiating agents as described here are molecularly targeted agents that affect tumorigenesis, often by modulating apoptosis. These agents include heat shock protein (HSP) inhibitors, in particular HSP90 inhibitors (HSPi). HSP90 is a molecular chaperone which stabilizes a variety of proteins required for survival of cancer cells. It is found to be overexpressed in a number of cancer types and therefore inhibition of HSP90 was identified as a potential therapeutic benefit in the treatment of multiple types of malignancies.
Researchers have demonstrated promising improvements in cancer treatment by administering free drug cocktails of a number of taxane/HSP90 inhibitors (HSP90i) combinations. Despite the advantages associated with the use of these free drug cocktails, there are various drawbacks that limit their efficacy including extensive gastrointestinal and ocular toxicity. In addition, administration of the free drug cocktails often results in rapid clearance of one or both of the agents before reaching the target site.
The RAS/RAF/MEK/ERK (Extracellular Signal-Regulated Kinases) pathway is one of the most well-known intracellular pathways and is regulated by receptor tyrosine kinases, cytokines, and heterotrimeric G-protein-coupled receptor. The series of proteins making up this pathway beings with a receptor on the surface of the cell and then transfers information intracellularly through subsequent proteins to the DNA within the nucleus. The pathway includes proteins such as, MAPK (mitogen-activated protein kinases, also called ERK), which communicate by adding phosphate groups to a neighboring protein, and in turn acts as an “on” or “off” switch. When one of the proteins in the pathway is mutated, it can become stuck in the “on” or “off” position—this is a necessary step in the development of many cancers. Components of the MAPK/ERK pathway were discovered when they were found in cancer cells. Numerous drugs that reverse the “on” or “off” switch are being investigated as cancer treatments.
The PI3K/AKT/mTOR or phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is another well-known intracellular signaling pathway that is central to cell growth and survival, cell cycle regulation, and programmed cell death. Abnormal activation of this signaling cascade is linked to several disease states, including the majority of human cancers, and therefore many components of the pathway are targets for therapeutic intervention. The PI3K/AKT/mTOR pathway plays a key role in cell proliferation, adhesion, migration, invasion, metabolism, and survival as well as angiogenesis. There are many known factors that enhance this pathway including, EGF, shh, IGF-1, insulin, and CaM; and there are many factors known to inhibit this pathway including PTEN, GSK3B, and HB9.
Researchers have demonstrated promising improvements in cancer treatment by administering free drug cocktails of a number of inhibitors of these pathways. Despite the advantages associated with the use of these free drug cocktails, there are various drawbacks that limit their efficacy including extensive gastrointestinal and ocular toxicity. In addition, administration of the free drug cocktails often results in rapid clearance of one or both of the agents before reaching the target site.
To improve clearance, many anticancer drugs in general have been incorporated into delivery vehicles designed to ‘shield’ them from mechanisms that would otherwise result in their rapid clearance from the bloodstream. It is well known that nanoparticles have the ability to provide this ‘shielding’ effect and they are thus often able to extend the half-life of therapeutic agents as well as reduce their toxicity and/or associated drug resistance. Encapsulation into well-designed delivery vehicles can also result in coordinated pharmacokinetics of encapsulated drugs. However, formulation of specific drugs or more than one drug into delivery vehicles has proven to be difficult because the polymer composition of the vehicle often differentially affects the pharmacokinetics of individual drugs. Thus a composition that is suitable for retention and release of one drug may not be suitable for the retention and release of a second drug. Presently, although some active combinations of inhibitors to these pathways are being successfully utilized in clinical trials, a pharmaceutical preparation designed to reduce toxicity and control the pharmacokinetics, and thus tumor delivery, of these drugs has not been described.
PCT publication WO2006/014626 ('626) describes particulate constructs for release of active agents of various kinds. In the nanoparticles of this publication, prodrugs wherein a therapeutic moiety is coupled through a linker to a hydrophobic moiety are assembled into nanoparticles using an amphiphilic stabilizer. The formulations are designed to coordinate release of free drugs from the particles by virtue of hydrolysis of a cleavable bond in the linker that results in the free drug being released from the particles. This is in contrast to the present invention wherein the nanoparticles are designed so as to release the prodrugs in intact form with subsequent hydrolysis in the bloodstream. This subset of the nanoparticles described in the '626 publication results from the appropriate selection of copolymer and the specific ratio of hydrophobic to hydrophilic portion as well as the required range of molecular weights of the hydrophobic portion and the size of the nanoparticles. This results in a different behavior from that focused on in the nanoparticles of the '626 publication.
The present inventors have identified for the first time particular nanoparticle formulations comprising combinations of drugs that result in extended half-lives, reduced toxicity, reduced drug resistance and/or superior efficacy when administered in vivo. Particular illustrative drug combinations include taxane or derivatives thereof and an HSP90 inhibitor and combinations of a RAS/RAF/MEK/ERK inhibitor and a PI3K/AKT/mTOR inhibitor.